ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.3706C>T (p.Arg1236Cys)

gnomAD frequency: 0.00061  dbSNP: rs151332923
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224065 SCV000281363 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Eurofins Ntd Llc (ga) RCV000224065 SCV000344096 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002478823 SCV000895028 uncertain significance Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3 2022-03-23 criteria provided, single submitter clinical testing
Invitae RCV001057372 SCV001221860 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1236 of the RPGRIP1L protein (p.Arg1236Cys). This variant is present in population databases (rs151332923, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of RPGRIP1L-related conditions and/or Meckel syndrome (PMID: 19430481, 31390572). ClinVar contains an entry for this variant (Variation ID: 235636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGRIP1L protein function. Experimental studies have shown that this missense change affects RPGRIP1L function (PMID: 31390572). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina RCV001118607 SCV001276902 uncertain significance Joubert syndrome 7 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001118608 SCV001276903 uncertain significance Meckel syndrome, type 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001118609 SCV001276904 uncertain significance Nephronophthisis 8 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001334835 SCV001527803 uncertain significance COACH syndrome 1 2018-05-07 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV000224065 SCV001823916 uncertain significance not provided 2023-06-21 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect; R1236C failed to rescue morpholino phenotype in zebrafish and another study demonstrated impaired binding to EML1 (Khanna et al., 2009; Uzquiano et al., 2019); Observed with a missense variant on the opposite allele (in trans) in a patient with subcortical heterotopia (Uzquiano et al., 2019); Observed in an individual with a clinical diagnosis of Meckel-Gruber syndrome without a second variant in the RPGRIP1L gene identified (Khanna et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19430481, 31390572, 34426522, 36068917, 36061204)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282064 SCV002570877 uncertain significance not specified 2022-07-15 criteria provided, single submitter clinical testing Variant summary: RPGRIP1L c.3706C>T (p.Arg1236Cys) results in a non-conservative amino acid change located in the RPGRIP1, C-terminal domain (IPR041091) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251036 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders (0.00055 vs 0.00079), allowing no conclusion about variant significance. c.3706C>T has been reported in the literature in an individual with a clinical diagnosis of Meckel syndrome but was heterozygous for this variant (Khanna_2009). Functional assessment for this variant in the zebrafish model was pathogenic (Khanna_2009). In a seperate study the variant impaired subcellular localization and interactions with EML1 (Uzquiano _2019). These reports do not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity Omics RCV000224065 SCV003811890 uncertain significance not provided 2021-11-19 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003407765 SCV004114967 uncertain significance RPGRIP1L-related condition 2023-05-30 criteria provided, single submitter clinical testing The RPGRIP1L c.3706C>T variant is predicted to result in the amino acid substitution p.Arg1236Cys. This variant has been reported in an individual with Meckel syndrome in the absence of a second variant (Khanna et al. 2009. PubMed ID: 19430481) as well as in a fetus with Meckel syndrome in the compound heterozygous state to a likely pathogenic variant (Moreno-Leon et al. 2022. PubMed ID: 36061204). This variant has also been reported in the compound heterozygous state in an individual with subcortical heterotopia (Uzquiano et al. 2019. PubMed ID: 31390572). This variant is reported in 0.095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-53639522-G-A). While we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV001271270 SCV001452343 uncertain significance Familial aplasia of the vermis 2020-09-16 no assertion criteria provided clinical testing

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